Royo is mostly known for his starring role on the HBO crime-drama series The Wire as the drug addict and confidential informant Reginald "Bubbles" Cousins, a regular character since the show's first season. Royo's portrayal of this character was so convincing that, during on-location filming, he was once approached by a Baltimore resident and given a small package of heroin, with the man saying to the in-character Royo: "Man, you need a fix more than I do." Royo has called this incident his "street Oscar."[5]

In 2012, Royo appeared in the NBC police drama Prime Suspect as Santana Cordero, an accused murderer killing witnesses before he was tried. He appears in the 2012 film Red Tails as Antwan "Coffee" Coleman. Royo then starred as a bully's alcoholic father in a Key & Peele sketch. In 2013, Royo portrayed geometry teacher Mr. Aster in the 2013 romantic-comedy drama film The Spectacular Now. He then was a guest voice in the Bob's Burgers episode "Nude Beach" playing himself, and then voiced an exterminator named Marcus in a 2014 episode titled "Tina and the Real Ghost". He is set to appear in the 2015 drama film Lila & Eve, as a character named Skaketti, alongside Jennifer Lopez and Viola Davis.

In 2015, Royo appears in Marvel's Agent Carter series portraying Spider Raymond, who ran the night club "La Martinique", but he became more notorious for being an illegal trader. He also appears in Showtime's Happyish as Barry, mutual friend of the main characters, Thom and Lee Payne.